There may be added value in the cohort managed on insulin, but these results were not powered to reach statistical importance. When indirectly analysed, there is a significant benefit in reduction of events of MI with prasugrel compared with ticagrelor in the diabetes patient group; with a trend to superiority relating to primary clinical outcomes, especially in those undergoing PCI.
Possible mechanisms
The clinical outcomes of patients with diabetes with ACS on clopidogrel monotherapy are superior to those on aspirin.37 It is therefore not surprising that when clopidogrel is combined with aspirin the outcomes are favourable in reduction of ischaemic events, versus placebo with aspirin. Patients with diabetes are more likely to be resistant to aspirin,39 and in addition, have increased P2Y12 receptor signalling.14 Therefore, this cohort may have amplified benefit from the addition of a P2Y12 receptor antagonist to the thromboxane A2 inhibitor aspirin compared to their non-diabetes counterparts.
Patients with diabetes have a higher level of platelet reactivity compared to the non-diabetes population.4 So the search for more potent inhibitors is especially important in this group. We have demonstrated from the analysis, that prasugrel and ticagrelor are superior to both placebo and clopidogrel. Regarding the newer agents versus clopidogrel, these findings are supported by trials of platelet function testing showing increased inhibition of aggregation with less variable response.40 This is likely to be multifactorial, but a large contributory is non-response to clopidogrel. Research shows that depending on method of assessment, 38–44% of patients with diabetes are non-responders to clopidogrel compared to 8–17% of patients without diabetes at 24 h.6 The level of poor response is still apparent at 7 days (24–53%),21 ,40 and is combined with lower levels of circulating active clopidogrel metabolite.21 ,41
Non-response to clopidogrel is a well-documented phenomenon attributed to a number of plausible factors such as increased clearance, reduced absorption altered metabolism to the active clopidogrel metabolite, and higher platelet turnover.3 Also, potential genetic factors have been linked possibly related to the abnormalities in CYP expression in the diabetes patient population.42 However, the predominant mechanism appears to be the abnormal metabolism of clopidogrel within the diabetes patient population rather than dysfunction of the P2Y12 receptor or its signalling pathway, as ex-vivo addition of active metabolite results in almost complete normalisation of response compared to controls.21 ,41
In non-responders, increased on-medication platelet reactivity is significantly correlated to major adverse cardiovascular events (CV death, ACS or stroke), with an increase in event rate from 13.2% to 37.7% at 2 years in patients with diabetes whose level of platelet reactivity is in the upper fourth quartile.43 Concern over non-responders/subresponders led to exploration of high-dose clopidogrel (150 mg) in the patient with diabetes. Although this did significantly reduce platelet aggregation, nonetheless, the majority remained categorised as a subresponder,44 which may explain the lack of statistically important benefit to double-dose clopidogrel in clinical outcomes.34
This has solidified the potential importance of the newer agents, prasugrel and ticagrelor. In the general population, they have been shown to be superior to clopidogrel in suppression of aggregation,20 ,45 ,46 even in those where patients are subjected to double-dose clopidogrel.40 Contributory to this is the reduced requirement of metabolism of prasugrel and ticagrelor, which decreases the time of onset of action and also limits the potential for drug interactions. Ticagrelor itself is a directly acting reversible agent,23 whereas prasugrel, a thienopyridine, requires a single rapid hydrolysation step to active metabolite. Interestingly, higher circulating esterases are found in patients with diabetes,39 which, in theory, would ameliorate this activation step, while inversely it would enhance clopidogrel’s conversion to inactive metabolite.3
The diabetes patient population requiring insulin therapy is trending towards increased benefit from the newer medications. As aforementioned, this represents a marker of severity and duration of diabetes, and functional studies have shown a muted response to clopidogrel in patients treated with insulin compared to oral medication.47 This would suggest that the insulin-dependent group would have added benefit from a more potent P2Y12 inhibitor. Further to this, insulin has been noted in vitro to reduce platelet aggregation by inhibition of the P2Y12 receptor, which, paradoxically, is in agreement with the findings of the review, as patients requiring insulin therapy are those who are most highly resistant to insulin.47
Against the results of this clinical outcome analysis favouring prasugrel are small studies of platelet reactivity testing. These studies have suggested superiority of ticagrelor over prasugrel at 5–30 days48–50 even in the DM-specific population.51 Thirty patients with diabetes undergoing PCI following an admission with ACS were evaluated in a prospective, single-blinded, single-centre crossover study comparing ticagrelor with prasugrel. All patients were preloaded with clopidogrel, and platelet reactivity was tested at days 0, 15 and 30 using VerifyNow P2Y12 functional assay. On day 15, patients were crossed over to the alternative comparator. The authors concluded that ticagrelor achieved a significantly higher level of platelet inhibition compared to prasugrel at 30 days. Possible explanations are the pretreatment with alternative thienopyridine to prasugrel (clopidogrel), although as the authors point out, this is more consistent with clinical practice, and the lack of washout period. Notably, prior to the crossover of patient groups from one comparator to the other, the difference in level of platelet inhibition was not statistically important.51 Does this mean reversible versus non-reversible agents would skew the results? Agreement in the discussion is reached that this is only functional testing, and may not relate to clinical outcomes, particularly as small population functional tests do not per se correlate with large study clinical outcomes.52 It does, however, raise the question of possible alternative pathways unrelated to platelet reactivity being involved. Furthermore, theoretically, ticagrelors’ functional superiority might be at the expense of a higher bleeding risk,48 however, no clinical outcome evidence was found in the analysis to support this.
The variation between the direct functional and indirect clinical findings solidifies the need for a direct comparison study between ticagrelor and prasugrel, with robust clinical and safety end points. We therefore await with great anticipation the results of the ISAR REACT 5 randomised control study,53 which will directly compare ticagrelor and prasugrel in those presenting with ACS undergoing an invasive strategy. The DM population is a clear prespecified subgroup, although patients with DM will be likely under-represented in this invasive study.23
Guidance
ESC and AHA both have clear guidance about antiplatelet management in ACS, with published guidelines for patients presenting with both non-ST elevation ACS (NSTE-ACS) and ST segment elevation MI (STEMI), all supporting the use of P2Y12 blockade in addition to aspirin (Class IA). There is already a move based on results of the landmark trials reviewed towards isolated guidance for patients with diabetes.17 ,54–57
The 2011 ESC guidelines support the preferential use of prasugrel in the diabetes patient population if P2Y12 antagonist naive and due to undergo PCI for NSTE-ACS, assuming patients are not at high risk of life-threatening bleeding.17 ,57 No specific preference is suggested in the STEMI group, where, generally, prasugrel and ticagrelor are favoured over clopidogrel.54
There are differing views in the 2014 ACCF/AHA (American College of Cardiology Foundation) NSTE-ACS guidelines, which state that with regard to antiplatelet therapy, patients with diabetes should be managed identically to the cohort without diabetes. They support the use of clopidogrel or ticagrelor (IB) with preference to ticagrelor, where the patient is undergoing early invasive or ischaemia-guided strategy. Prasugrel is not recommended for upfront therapy in any patient with ACS, unless undergoing PCI, and not at high risk of bleeding.55 In the 2013 ACCF/AHA STEMI guidelines, all P2Y12 inhibitors are given the same level of evidence without preference. But a minor comment is made to consider prasugrel in younger patients with DM with low bleeding risk, ability to continue dual antiplatelet therapy, and no planned surgery in the next year.56
In 2014, the UK National Institute for Health and Care Excellence (NICE) has followed suit with support for prasugrel in the diabetes patients cohort that present with ACS (STEMI and NSTE-ACS included), and who have a planned invasive strategy.58 They determined that in comparison to clopidogrel, prasugrel is judged to be the dominant treatment; as it is not only more effective in reducing subsequent events, it actually costs less than clopidogrel when given to patients with diabetes with NSTE-ACS managed within the UK National Health Service framework.
Our findings support the advice from NICE, and we await future guidelines from AHA/ESC with regard to a more tailored approach to ACS management.
Strengths and limitations
The original studies included in this analysis were large multicentre randomised controlled trials with careful prespecification of the DM subgroup in the majority.7 ,22 ,23 ,34 All the studies were found to have low risk of bias using the Cochrane risk of bias tool detailed in online supplementary appendix 1. However, the analysis is restricted to published literature, all in peer-reviewed journals, but an element of publication bias cannot be excluded. Further papers where we cannot exclude ad hoc subgroup analysis are at risk of statistical error.8 ,19 ,32
The definition of DM is not clearly explored in every study population, which may be open to differing interpretation. Four clearly state previous diagnosis of diabetes was required; however, this was only inferred in others. Only PLATO has analysed data on all participants on the basis of HbA1c which would enable pick up of patients previously undiagnosed with DM, arguably those at highest risk.
Indirect comparison analysis does require homogeneity of those compared, which is supported by the findings of the Cochrane Q statistics observing absence of heterogeneity in the clopidogrel versus control group. Random effects relative risk was required for the combination risk of prasugrel compared to clopidogrel in light of heterogeneity, which needs to be taken into account when considering the primary outcome indirect comparison. However, the remaining outcomes indirectly compared are single-study comparisons with similar design. In the analysis of major bleeding risk, we used results generated from identical scoring schemes (TIMI) to maximise homogeneity.